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rdf:type |
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lifeskim:mentions |
umls-concept:C0018787,
umls-concept:C0030685,
umls-concept:C0033414,
umls-concept:C0220905,
umls-concept:C0255156,
umls-concept:C0391871,
umls-concept:C0599894,
umls-concept:C0678227,
umls-concept:C0680255,
umls-concept:C1283071,
umls-concept:C1419779,
umls-concept:C1514559,
umls-concept:C1704708,
umls-concept:C1711351,
umls-concept:C1963578,
umls-concept:C2349975
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pubmed:issue |
4
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pubmed:dateCreated |
2009-2-27
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pubmed:abstractText |
MicroRNAs are small endogenous noncoding RNAs that regulate protein expression by hybridization to imprecise complementary sequences of target mRNAs. Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure. However, the specific molecular targets and cellular mechanisms involved in the action of miR-1 in the heart are only beginning to emerge. In this study we investigated the effects of increased expression of miR-1 on excitation-contraction coupling and Ca(2+) cycling in rat ventricular myocytes using methods of electrophysiology, Ca(2+) imaging and quantitative immunoblotting. Adenoviral-mediated overexpression of miR-1 in myocytes resulted in a marked increase in the amplitude of the inward Ca(2+) current, flattening of Ca(2+) transients voltage dependence, and enhanced frequency of spontaneous Ca(2+) sparks while reducing the sarcoplasmic reticulum Ca(2+) content as compared with control. In the presence of isoproterenol, rhythmically paced, miR-1-overexpressing myocytes exhibited spontaneous arrhythmogenic oscillations of intracellular Ca(2+), events that occurred rarely in control myocytes under the same conditions. The effects of miR-1 were completely reversed by the CaMKII inhibitor KN93. Although phosphorylation of phospholamban was not altered, miR-1 overexpression increased phosphorylation of the ryanodine receptor (RyR2) at S2814 (Ca(2+)/calmodulin-dependent protein kinase) but not at S2808 (protein kinase A). Overexpression of miR-1 was accompanied by a selective decrease in expression of the protein phosphatase PP2A regulatory subunit B56alpha involved in PP2A targeting to specialized subcellular domains. We conclude that miR-1 enhances cardiac excitation-contraction coupling by selectively increasing phosphorylation of the L-type and RyR2 channels via disrupting localization of PP2A activity to these channels.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic beta-Agonists,
http://linkedlifedata.com/resource/pubmed/chemical/B56alpha protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Benzylamines,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channels, L-Type,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium-Calmodulin-Dependent...,
http://linkedlifedata.com/resource/pubmed/chemical/Isoproterenol,
http://linkedlifedata.com/resource/pubmed/chemical/KN 93,
http://linkedlifedata.com/resource/pubmed/chemical/MicroRNAs,
http://linkedlifedata.com/resource/pubmed/chemical/Mirn1 microRNA, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Phosphatase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Ryanodine Receptor Calcium Release...,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1524-4571
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
27
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pubmed:volume |
104
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
514-21
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pubmed:dateRevised |
2011-9-22
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pubmed:meshHeading |
pubmed-meshheading:19131648-Adenoviridae,
pubmed-meshheading:19131648-Adrenergic beta-Agonists,
pubmed-meshheading:19131648-Animals,
pubmed-meshheading:19131648-Arrhythmias, Cardiac,
pubmed-meshheading:19131648-Benzylamines,
pubmed-meshheading:19131648-Calcium Channels, L-Type,
pubmed-meshheading:19131648-Calcium Signaling,
pubmed-meshheading:19131648-Calcium-Calmodulin-Dependent Protein Kinase Type 2,
pubmed-meshheading:19131648-Cells, Cultured,
pubmed-meshheading:19131648-Genetic Vectors,
pubmed-meshheading:19131648-Isoproterenol,
pubmed-meshheading:19131648-Membrane Potentials,
pubmed-meshheading:19131648-Mice,
pubmed-meshheading:19131648-MicroRNAs,
pubmed-meshheading:19131648-Myocardial Contraction,
pubmed-meshheading:19131648-Myocytes, Cardiac,
pubmed-meshheading:19131648-Phosphorylation,
pubmed-meshheading:19131648-Protein Kinase Inhibitors,
pubmed-meshheading:19131648-Protein Phosphatase 2,
pubmed-meshheading:19131648-Rats,
pubmed-meshheading:19131648-Ryanodine Receptor Calcium Release Channel,
pubmed-meshheading:19131648-Sarcoplasmic Reticulum,
pubmed-meshheading:19131648-Sulfonamides,
pubmed-meshheading:19131648-Time Factors,
pubmed-meshheading:19131648-Transduction, Genetic
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pubmed:year |
2009
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pubmed:articleTitle |
miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2.
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pubmed:affiliation |
Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, Ohio State University, Columbus, OH 43210, USA. Dmitry.Terentyev@osumc.edu
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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